Human Microbiome Inspired Antibiotics with Improved β-Lactam Synergy against MDR Staphylococcus aureus

John Chu, Xavier Vila-Farres, Daigo Inoyama, Ricardo Gallardo-Macias, Mark Jaskowski, Shruthi Satish, Joel S. Freundlich, Sean F. Brady

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

The flippase MurJ is responsible for transporting the cell wall intermediate lipid II from the cytoplasm to the outside of the cell. While essential for the survival of bacteria, it remains an underexploited target for antibacterial therapy. The humimycin antibiotics are lipid II flippase (MurJ) inhibitors that were synthesized on the basis of bioinformatic predictions derived from secondary metabolite gene clusters found in the human microbiome. Here, we describe an SAR campaign around humimycin A that produced humimycin 17S. Compared to humimycin A, 17S is a more potent β-lactam potentiator, has a broader spectrum of activity, which now includes both methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus faecalis (VRE), and did not lead to any detectable resistance when used in combination with a β-lactam. Combinations of β-lactam and humimycin 17S provide a potentially useful long-term MRSA regimen.

Original languageEnglish (US)
Pages (from-to)33-38
Number of pages6
JournalACS Infectious Diseases
Volume4
Issue number1
DOIs
StatePublished - Jan 12 2018
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by NIH U19AI109713. We thank the following laboratories and facilities for strains and technical support: Rockefeller University, Tomasz Lab (S. aureus), Fischetti Lab (S. aureus), Hang Lab (Enterococcus species), and High-Throughput and Spectroscopy Resource Center (NMR); Memorial Sloan Kettering Cancer Center, NMR Analytical Core Facility (HRMS).

Keywords

  • MRSA
  • NRPS
  • Syn-BNP
  • antibiotics
  • β-lactam

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